Between 2-5% of the population develops diabetes mellitus and 20-30% of diabetics develop diabetic nephropathy. The latter accounts for over 30 % of end-stage renal failure (E.S.R.F.) requiring dialysis or transplantation in western society. The pathological hallmark of diabetic nephropathy is glomerulosclerosis due to accumulation of extracellular matrix proteins in the glomerular mesangium. Mesangial matrix accumulation reflects both increased synthesis and decreased degradation of extracellular matrix (ECM) components, and correlates with the clinical onset of proteinuria, hypertension and progressive kidney failure. Hyperglycaemia is a major stimulus for mesangial cell matrix production in diabetic nephropathy. The mechanisms by which hyperglycaemia perturb mesangial cell function are still being appreciated and include direct effects of high extracellular glucose levels and indirect effects transduced through alterations in glomerular haemodynamics and through the actions of advanced glycosylation end products.
Propagation of mesangial cells under conditions of high ambient glucose has proved a useful in vitro model with which to probe the molecular basis for mesangial matrix accumulation in diabetes, attributable to hyperglycaemia. Specifically, exposure of cultured mesangial cells to high glucose stimulates de novo synthesis of ECM components, such as type IV collagen, fibronectin and laminin, and other products that are accumulated in vivo (Ayo, S. H., et al. (1990) Am.J. Pathol. 136, 1339-1348; Wahab, N. A., et al. (1996) Biochem. J. 316, 985-992; and Ayo, S. H., et al. (1991) Am. J. Physiol. 260, F185-F191).
In view of the high morbidity and mortality rate from diabetic nephropathy in diabetics there is a need to identify stimuli which affect the onset and progression of diabetic nephropathy with the aim of preventing such onset or inhibiting or limiting the progression thereof.